tbuckley/cabot-search huggingface dataset:
Blood gene expression changes in metastatic lung cancer under first-line immunotherapy according to clinical response.
Authors: Fabienne Lusky, Hannah Schindler, Mariam Elshiaty, Lena Gaissmaier, Lea Daniello, Farastuk Bozorgmehr, Jonas Kuon, Rajiv Shah, Marc A Schneider, Florian Eichhorn, Philip Baum, Franziska Trudzinski, Arlou Angeles, Florian Janke, Martina Kirchner, Daniel Kazdal, Albrecht Stenzinger, Holger Sültmann, Michael Thomas, Petros Christopoulos
Journal: Journal of Clinical Oncology (2022)

e21141 Background: First-line pembrolizumab monotherapy is a standard treatment for metastatic non-small-cell lung cancer (NSCLC) with high PD-L1 expression (TPS ≥50%). However, many patients do not respond, and reliable biomarkers are lacking. Methods: Blood samples of 33 patients with metastatic NSCLC were analyzed at baseline (BL) and after four cycles of pembrolizumab monotherapy (FU). The expression of 12 genes involved in tumor-specific immune responses ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, MKI67, TBX21) in whole blood RNA was quantified by RT-PCR in absolute terms using plasmids as standards. Results: Gene expression was significantly higher after immunotherapy for 11/12 genes analyzed ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21 with fold changes [FC] 1.99 – 5.45; all p &lt; 0.001). Blood neutrophil and total leukocyte counts were significantly decreased (ANC BL:7.65/nl vs. FU:5.36/nl, p = 0.024; Leu BL:10.65/nl vs. FU:7.78/nl, p = 0.032), while lymphocyte counts did not change (ALC BL:1.41/nl vs. FU:1.47/nl, p = 0.267). Increases in the expression of RORgt, FASLv1, PRF1, PD1, CD247, GZMB and TBX21 remained significant (FC 1.9 – 3.7; all p &lt; 0.001) even after correction for the blood lymphocyte/leukocyte ratio (Ly/Lc BL:0.151 vs. FU:0.197, p = 0.003). Patients with long-term response (LTR, i.e. lasting &gt; 6 months) had significantly higher increases in the expression of 8 genes ( RORgt, FOXP3, IFNγ, FASLv1, GATA3, PD1, CD247, TBX21) compared with patients with rapid disease progression within 3 months (RP) (FC 2.34 – 4.62, all p &lt; 0.05). There were no significant differences (FU-BL) between LTR and RP regarding ANC (RP:-1.00/nl vs. LTR:-2.63/nl, p = 0.50), ALC (RP:-0,14/nl vs. LTR:+0,12/nl, p = 0,33) or Ly/Lc (RP:0.015 vs. LR:0.0542, p = 0.259). Conclusions: Pembrolizumab monotherapy of metastatic NSCLC causes significant increases in the blood expression for several genes including FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21, as well as a decrease in circulating neutrophiles and total leucocytes. Long-term responders have more pronounced blood gene expression changes, which appear to correlate with long-term benefit, in contrast to blood count changes, which are not indicative. These results are currently being validated in a larger prospective study.
<i>ANK2 </i>mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Hongbing Liu, Lele Zhao, Yaqin Liu, Mingzhe Xiao, Qin Zhang, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e21080 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple cancers, in particular with non-small cell lung cancer (NSCLC). However, only a minority of patients could benefit from ICIs. Therefore, investigating predictive biomarkers of ICIs is important to identify the target population that derives the best therapeutic benefit. ANK2 encodes ankyrin-2, which plays a crucial role in cell development. Studies have shown a significant correlation between ANK2 expression levels and clinical outcomes in gastrointestinal cancers and pancreatic cancer. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to demonstrate the association between ANK2 and ICIs. Methods: 165 patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between ANK2 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: Patients with ANK2 mutation were significantly associated with better PFS (HR = 0.28; 95% CI, 0.15-0.53; P &lt; 0.001), objective response rate (ORR, 69.0% vs 24.3%; P &lt; 0.001) and durable clinical benefit (DCB, 72.4% vs 41.9%; P = 0.003) compared with those with wide-type in NSCLC. ANK2 mutation were associated with increased TMB (P &lt; 0.001). In the multivariable Cox proportional hazards regression model adjusted by the smoking status, PD-L1 expression and TMB, the association between ANK2 mutation and PFS remained significant (HR = 0.28; 95% CI, 0.20-0.82; P = 0.012).In TCGA, no association between ANK2 mutation and OS (LUAD: P =0.27 ; LUSC: P = 0.39) or PFS (LUAD: P = 0.21; LUSC: P = 0.63) was observed, suggesting that ANK2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, ANK2mutation was significantly associated with higher CD8+ T cells, higher M1 macrophage, and lower M2 macrophage. Moreover, ANK2 mutation was associated with increased TMB (P &lt; 0.001) and neoantigen load (P &lt; 0.001) in TCGA. In addition, GSEA analysis revealed that ANK2 mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway in LUAD. Conclusions: Our results demonstrated that ANK2 mutation is an independent classifier that could stratify patients with NSCLC for ICIs. The role of ANK2 in immunotherapy is needed to be further studied.
Novel use of ctDNA to identify muscle-invasive and non-organ-confined upper tract urothelial carcinoma.
Authors: Heather L Huelster, Elizabeth A. Green, Alex C. Soupir, Kyle M. Rose, Esther N. Katende, Shreyas U Naidu, Scott Michael Gilbert, Brandon J. Manley, Michael Adam Poch, Wade J. Sexton, Alice Yu, Philippe E. Spiess, Pan Du, Shidong Jia, Il-Jin Kim, Lu Tan, Liang Wang, Roger Li
Journal: Journal of Clinical Oncology (2022)

4587 Background: Upper tract urothelial carcinoma (UTUC) is an aggressive cancer for which use of neoadjuvant chemotherapy (NAC) is limited by suboptimal clinical staging prior to nephroureterectomy. Detection of circulating tumor DNA (ctDNA) is associated with locally advanced and metastatic urothelial carcinoma of the bladder and may help identify UTUC patients who would benefit from NAC. Here we examine the feasibility and utility of plasma ctDNA in the diagnosis of non-organ confined high-risk UTUC. Methods: Patients with high-grade cTa-T2 UTUC without radiographic evidence of metastatic disease undergoing up-front radical nephroureterectomy (RNU) were prospectively accrued for pre- and post-operative plasma collection. Blood was collected preoperatively on the day of surgery, and plasma and buffy coat were processed for extraction of cell-free DNA and genomic DNA, respectively. FFPE tumor samples from RNU were used for tissue genomic DNA extraction. Targeted next-generation sequencing (NGS) was used for variant profiling. ctDNA positivity was defined as the presence of plasma cell-free DNA variants concordant with tissue-based variants. Results: NGS analyses of matched FFPE and plasma samples were successfully performed for all 19 accrued UTUC patients. Alterations in the TERT promoter (74%), TP53 (58%), FGFR3 (53%), myc amplification (53%), and ATM (42%) were demonstrated in urothelial tumor tissue. Matched plasma ctDNA showed prevalent alterations in the TERT promoter (42%), TP53 (42%), PIK3CA (37%), ATM (32%) and CD274 (26%). Nine patients (47%) had detectable plasma ctDNA mutations concordant with tumor-specific variants using the targeted NGS panel. All patients with detectable preoperative ctDNA had advanced staging (≥pT2 or ≥pN1) and lymphovascular invasion on final pathology, resulting in a 90% sensitivity. The panel was 100% specific with no patients with pTis, pTa, pT1 and pN0 having detectable concordant ctDNA mutations. Concordant plasma ctDNA was detected in four of nine patients postoperatively. Two of three (67%) who developed metastatic disease had detectable ctDNA while neither of the two who developed non-muscle-invasive bladder recurrences did. Conclusions: Prospective ctDNA analysis using a targeted NGS panel can be used to predict muscle-invasive and non-organ-confined UTUC preoperatively. Detectable postoperative ctDNA may indicate residual disease and predate clinical recurrence.
Genetic mutations-based criteria to distinguish multiple primary lung cancers from intrapulmonary metastasis in patients with lung tumors.
Authors: Zhenhua Li, Huilai Lv, Fan Zhang, Ziming Zhu, Qiang Guo, Mingbo Wang, Chao Huang, Lijie Guo, Fanfei Meng, Shaohua Yuan, Xiaoliang Shi, Ziqiang Tian, Fei Pang
Journal: Journal of Clinical Oncology (2022)

e21038 Background: Patients with multiple primary lung cancers (MPLC) and intrapulmonary metastasis (IPM) are considered as different clinical stages and require different treatment strategies. At present, the molecular identification criteria employed for distinguishing MPLC and IPM still need to be improved. Therefore, there is an unmet medical need in regards to a diagnostic standard that could effectively distinguish MPLC from IPM. Methods: Between December 2014 and April 2020, a total of 35 patients, with more than two lung lesions, were selected and divided into a training cohort (N = 22) and a validation cohort (N = 13). Imaging, anatomical evidence, pathological results, and histological examinations of the primary tumor, as well as histological subtypes, were used to differentiate MPLC from IPM. Genomic profiles obtained using a targeted sequencing with 450 cancer-related genes panel were analyzed. Modified diagnostic criteria for MPLC and IPM were established based on Martini and Melamed criteria, as well as molecular profiles. Results: We developed interpretation criteria using a flowchart that distinguishes MPLC from IPM, as follows: 1) MPLC can be determined using the following aspects: no common mutations are present; one lesion has no mutations (tumor = 2); two common high frequency driver gene mutations are present, or one driver gene mutation and one rare mutation comprising the p53 mutation are present; and only one common mutation is present. 2) IPM can be determined using the following aspects: one driver gene mutation and one rare mutation comprising the p53 mutation (concordance rare ≥ 50%) are present; two driver gene mutations (concordance rare ≥ 60%) are present; all mutations are common; and more than three common mutations are present. 3) Undetermined results are based on the following aspects: no mutations in one tumor are present (tumor &gt; 2); no mutations are identified in all tumors; or two rare mutations are present. Undetermined patients were identified by combining histological identifications. Subsequently, to verify the criteria, 13 patients were recruited as a validation cohort. Eight MPLC and 5 IPM patients were identified, and the results were 100% consistent with independent imaging and pathological diagnoses. Conclusions: In this work, we proposed more comprehensive and detailed molecular identification criteria for MPLC and IPM, and it suggested that genetic alterations may be an effective method for diagnosing MPLC and IPM. We also determined that NGS may be a useful tool for assisting with differential diagnoses. Key words: Multiple lung cancer, Multiple primary lung cancer, Intrapulmonary metastasis, Next-generation sequencing, molecular classification.
Locoregional therapy trends by frailty and life expectancy in older adults with T1N0 hormone receptor-positive breast cancer.
Authors: Christina Ahn Minami, Ginger Jin, Rachel A. Freedman, Mara A. Schonberg, Tari A. King, Elizabeth A. Mittendorf
Journal: Journal of Clinical Oncology (2022)

12047 Background: Women &gt;70 years old with T1N0 hormone receptor-positive (HR+) breast cancer face complex locoregional therapy decisions, as breast surgery type, and omission of axillary surgery or radiation therapy (RT), do not impact overall survival. Although frailty status and life expectancy (LE) ideally factor into therapy decisions, their impact on decision-making is unclear. We sought to identify trends in, and factors associated with locoregional therapy type by frailty and LE, and to determine if therapy type was associated with cause of death. Methods: Women &gt;70 years old with T1N0 HR+/HER2-negative breast cancer diagnosed 2010-2015 were identified in SEER-Medicare. Stratified by validated claims-based frailty (Kim et al) and LE (Tan et al) measures, trends in therapy (lumpectomy, lumpectomy + axillary surgery, lumpectomy + RT, mastectomy, lumpectomy + axillary surgery + RT, and mastectomy + axillary surgery, with the last two combinations deemed “more intense” therapy) were analyzed. Generalized linear mixed models were used to identify factors associated with therapy receipt (breast surgery type, axillary surgery, and RT) and, among the women who died in this cohort, to explore potential associations between local therapy received and cause of death. Results: Of the 16,188 women included, 21.8% were frail, 22.2% had a LE&lt;5 years, but only 12.3% were both frail and had a LE&lt;5 years. In frail women who had a LE &lt; 5 years, more intense therapy regimens decreased significantly (lumpectomy + axillary surgery + RT: 27.5% to 17.3%, p&lt;0.001; mastectomy + axillary surgery: 20.8% to 13.9%, p=0.02) over the study period. However, in 2015, 30% of frail women with a LE&lt;5 years still underwent a more intense regimen. On multivariable analysis, frailty and LE&lt;5 years were associated with a lower likelihood of axillary surgery (frailty: OR 0.65, 95% CI [0.57-0.73]; LE&lt;5 years: OR 0.67, 95% CI [0.59-0.76]) and RT (frailty: OR 0.77, 95% CI [0.69-0.86]; LE&lt;5 years: OR 0.73, 95% CI [0.65-0.83]), but not with breast surgery type. Of the 1868 women who died, 306 (16.4%) died of breast cancer and those undergoing more intense therapy were as likely to die of breast cancer vs other causes (Table). Conclusions: In older women with T1N0 HR+ disease, rates of more intense therapy are decreasing but 30% of frail women with a limited LE still underwent more intense therapy in the final study year. As therapy intensity does not affect breast cancer-specific mortality, appropriate de-escalation of locoregional therapy is needed. [Table: see text]
The HERPET study: Imaging HER2 expression in breast cancer with the novel PET tracer [<sup>18</sup>F]GE-226, a first-in-patient study.
Authors: Laura M. Kenny, Fiona J Gilbert, Gosala Gopalakrishnan, Preetha Aravind, Tara Barwick, Neva Patel, Duncan ROBERT Hiscock, Istvan Boros, Steven Kealey, Franklin I Aigbirhio, Jingky Lozano-kuehne, Susan Jane Cleator, Ben Fleming, Pippa Riddle, Rizvana Ahmad, Sue Chua, Stephen R.D. Johnston, Janine Mansi, Gary J. Cook, Eric O. Aboagye
Journal: Journal of Clinical Oncology (2022)

3069 Background: Over-expression the human epidermal growth factor receptor-2 (HER2) is seen in 20% of breast cancers; this is an adverse prognostic factor and used to guide therapy selection. At present HER2 expression can only be determined using biopsy material using immunohistochemistry or fluorescence in situ hybridisation. Heterogeneous expression of HER2 is now being recognised as a cause of treatment resistance but is difficult to characterise. A non-invasive method for determining HER2 expression could have several advantages and help select appropriate therapy for patients. GE-226 is a novel radiolabelled GE-Affibody radioligand which binds to the HER2 receptor with high affinity at a different epitope than trastuzumab. Methods: Patients with locally advanced or metastatic breast cancer were recruited and scanned for 65 mins after iv injection of 200MBq of GE-226 (mean activity injected for each patient 202MBq (range 164-223MBq, mean radiochemical purity 94%) of radioligand, over one bed position for dynamic imaging, followed by a half-body scan. Blood sampling was used to measure metabolism of the tracer. Safety was assessed. HER2-extracellular domain (ECD) domain was measured in blood. Tumoural uptake was quantified by semi-quantitative and fquantitative parameters in HER2 positive and HER2 negative tumours. Patients had routine baseline FDG imaging. Results: Twenty patients completed the study. GE-226 scans were well tolerated. There were no serious adverse events. GE-226 was slowly metabolised into a single metabolite in the liver; 97% of parent remained at 60 minutes post injection (range 82-100). There was a significant difference in tumoural radioligand uptake between biopsy proven HER2 positive and HER2 negative tumoural patients as measured by SUV mean and SUV max (p &lt; 0.001). Comparing HER2 positive to HER2 negative cases, there was also a significant difference between tumour to normal tissue uptake ratios SUV mean . Heterogeneous uptake was observed in three patients, two with interlesional uptake variation and one with intralesional heterogeneity. Tumoural uptake increased over time. Normal physiological uptake in salivary glands and the thyroid gland was noted. GE-226 was able to differentiate between lymphadenopathy due to sarcoidosis and cancer in one patient and was superior to FDG which had shown widespread uptake in the benign and malignant nodes. Conclusions: [18F]GE-226 imaging is well tolerated and shows promise for imaging of HER2 positive breast cancer. Further studies with this agent are now planned. Clinical trial information: NCT03827317.
Real-world analysis of BRAF inhibitors with patients positive for BRAF V600E mutations diagnosed with rare tumors.
Authors: Zoya Peelay, Vijay Maruti Patil, Vanita Noronha, Shruti Pathak, Nandini Sharrel Menon, Kumar Prabhash
Journal: Journal of Clinical Oncology (2022)

e15085 Background: BRAF mutation is seen in multiple cancers and BRAF inhibitors have a tumor agnostic nature. However there is very limited real world data for BRAF inhibitors and hence we have performed this analysis. Methods: In Tata Memorial Hospital, the medical oncology solid unit 2 maintains a prospective database of all patients who undergo molecular testing. A query was raised from this database and 17 patients were identified who were BRAF mutant positive. The demographic details of these patients, the previous treatment details, the therapy received by these patients, the response to the therapy, the date of progression and the date of death was recorded. Descriptive statistics were performed and Kaplan-Meier analysis was used to estimate the progression-free survival (PFS) and overall survival (OS). Results: In all the 17 patients the mutation was BRAF V600E.The median age of the patients was 58 years (16-77). The m:f ratio was 13:4. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 9 patients (52.9%) and 2-3 in 8 patients (47.1%). The primary sites included in the analysis were lung cancer in 8 (47.1), glioma in 3 (17.7), thyroid in 2 (11.8%) and one each of parotid, melanoma, esophagus, thymoma. BRAF inhibitors could be provided in 9 patients (52.9%) and its was dabrafenib-trametinib in 8 patients and vemurafenib then dabrafenib-trametinib in 1 patient. The median progression free survival was 203 days (95% CI 25.1-380.9) and overall survival was 220 days (95% CI 49.8-408.2) . Conclusions: The real world data suggests that the efficacy of BRAF inhibitors seems to be lower than that seen in pivotal studies. The reasons for which is unknown.
Recurring event survival analyses: A methodological approach to model recurring event data in cancer patients receiving multiple lines of therapy.
Authors: Aaron Galaznik, William Dudley, Nicholas Coombs
Journal: Journal of Clinical Oncology (2022)

e18693 Background: In cancer treatment, patients often receive multiple rounds of treatment, or Lines of Therapy (LoT). The time between start of a LOT and change to a new LOT is an important outcome in clinical oncology, for understanding disease progression and anticipating response to further treatment. Research questions may focus on the associations between duration of an LOT (the dependent variable) and independent variables of interest, such as time-invariant demographic (gender, age, race) and clinical factors (comorbidities, stage of disease) as well as time-varying factors such as Patient Reported Outcomes (PRO’s), resource utilization, and adverse events. These associations can be tested empirically with traditional “survival analyses”, more generally known as time-to-event when there is a single event (such as 5-year survival). The analyses, however, may become more complex when patients experience more than one LOT. This is due to the possibility that the Time-to-Events may be correlated within an individual patient, similarly to how outcome variables are correlated in other repeated measures designs. If this correlation is not captured in the modeling, the validity of parameters estimates may be in doubt. Thus, it is important to analyze the data using methods which account for the within-person correlation among LOT durations through the use of “Recurring Event” survival analyses. Methods: This methodological presentation will report an example of a real world “Recurring Event” analysis in a study of Multiple Myeloma patients who received one or more than one LOT. The study data set was derived from users of PROmpt®, an application for remote patient reporting and provider symptom management. Patient characteristics and treatment history were assessed by survey and review of patient EMR records. 80 patients were identified, with a treatment history of receiving between 1 and 19 LOT’s (mean = 5.2). Time invariant predictors are age, gender, and frailty (employing the Modified Geriatric Assessment). Time varying variables are the incidence of hematological and non-hematological toxicities. Results: The presentation will provide: an overview of how to interpret the model parameters, a discussion of the data structure required by the modeling, and a series of results in which LOT durations are analyzed as first independent and then when modeled as a “Recurring Event” analysis. The results are examined across different modeling strategies to illustrate a model testing approach, as well as to quantitatively demonstrate the impact on survival analysis results when incorporating “recurring event” methodology. Conclusions: The intent of the presentation is to alert researchers to the need to analyze Time-To-Event models using a recurring event framework when patients experience recurring events in order to produce valid and generalizable parameters.